1. Field of the Invention
The present invention relates to the field of methods and compositions for the treatment of hypotension. The invention also relates to the field of combination therapeutic regimens particularly those which include a regimen of a particularly tailored parenteral formulation. The present invention also relates to the field of anti-tumor necrosis factor antibodies, as well as anti-endotoxin antibodies and interleukin-1 receptor antagonists as part of a therapeutic regimen for the treatment of hypotension, septic shock and related conditions.
2. Background of the Related Art
In 1980, Furchgott and Zawadski (Nature 288:373-376) demonstrated that endothelial cells, which line blood vessels, can be stimulated to release a substance which relaxes vascular smooth muscle i.e., causes vasodilatation. Since the chemical nature of this substance was completely unknown, it was simply named endothelium-derived relaxing factor (EDRF). It is now widely accepted that many naturally-occurring substances which act as physiological vasodilators mediate all or part of their action by stimulating release of EDRF; these substances include, acetylcholine, histamine, bradykinin, leukotrienes, ADP, ATF, substance P, serotonin, thrombin and others.
Although the extremely short lifetime of EDRF (several seconds) hampered efforts to chemically identify this molecule, in 1987 several laboratories suggested that EDRF may be nitric oxide (NO). Nitric oxide is known to spontaneously decompose to nitrate and nitrite. A fundamental problem in accepting this NO hypothesis was that mammalian systems were not known to contain an enzymatic pathway which could synthesize NO; additionally, a likely precursor for NO biosynthesis was unknown. After observing that the arginine analog L-N.sup.G -methylarginine (L-NMA) could inhibit vascular EDRF/NO synthesis induced by acetylcholine and histamine, and that EDRF/NO synthesis could be restored by adding excess L-arginine, certain of the present inventors proposed that arginine is the physiological precursor of EDRF/NO biosynthesis (Sakuma et al. (1988), PNAS, 85:8664-8667). Certain of the present inventors later demonstrated that inhibition of EDRF/NO synthesis in the anesthetized guinea pig raises blood pressure (Aisaka et al. (1989), BBRC 160:881-886). This information further suggested to the inventors that EDRF/NO was an important physiological regulator of blood pressure.
Other laboratories have reported that macrophage cells become "activated" by 12-36 hour treatment with gamma-interferon, bacterial endotoxin and various cytokines. This "activation" is associated with initiation of tumor cell killing and generation of nitrite and nitrate from L-arginine. It was observed that activated macrophages actually make NO from L-arginine (just like endothelial cells) and that this NO subsequently reacts with oxygen to form more oxidized nitrogen metabolites which appear to be physiologically inert (Stuehr et al. (1989), J. Exp. Med. 169:1011-1020).
Cytokines are well known to cause morphological and functional alterations in endothelial cells. These alterations occur in part as a result of "endothelial cell activation" Distinct immune-mediators such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and gamma-interferon (IFN) appear to induce different but partially overlapping patterns of endothelial cell activation including increased procoagulant activity (Bevilaqua (1986) PNAS, 83:4533-4537), PGI and 2 production (Rossi (1985), Science, 229:174-176), HLA antigen expression (Pober (1987) J. Immunol., 138:3319-3324) and lymphocyte adhesion molecules (Carender (1987) J. Immunol., 138:2149-2154). Although these cytokines are reported to cause hypotension, vascular hemorrhage, and ischemia, the underlying mechanisms of altered vasoactivity are unclear (Goldblum et al. 1989, Tracey et al. Science 234:470, 1986). A potential mediator of altered vasoactivity proposed by the present inventors is EDRF. A major dose limiting toxicity of these and other biological response modifiers is hypotension and vascular leakage (Dvorak (1989) J.N.C.I., 81:497-502). Thus, the clinical utility of these and other agents remains limited. A method for providing the therapeutic effects of these agents without the risk of potentially lethal side effects before the practical and widespread utilization of these agents can be realized by the medical community.
Septic shock, a life-threatening complication of bacterial infections, affects 150,000 to 300,000 patients annually in the United States (Parrillo, J. E. (1989), Septic Shock in Humans: Clinical Evaluation, Pathogenesis, and Therapeutic Approach (2nd ed.) In: Textbook of Critical Care. Shoemaker, et al., editors, Saunders Publishing Co., Philadelphia, Pa., pp. 1006). The cardiovascular collapse and multiple metabolic derangements associated with septic shock are due largely to bacterial endotoxin (ET), which has been shown to elicit a septic shock-like condition when administered to animals (Natanson, et al. (1989), Endotoxin and Tumor Necrosis Factor Challenges in Dogs Simulate the Cardiovascular Profile of Human Septic Shock, J. Exp. Med. 169:823).
ET is known to stimulate the synthesis and release of several cytokines and biological mediators having hypotensive activity. Among the factors released, TNF, PAF, prostacyclin and complement-derived C5a anaphylatoxin have been proposed as important contributors to the cardiovascular collapse of septic shock (Hesse, et al. (1988), Cytokine Appearance in Human Endotoxemia and Primate Bacteremia, Surg. Gynecol. Obstet., 166:147; Etienne, et al. (1986), The Relative Role of PAF-acether and Icosanoids in Septic Shock, Pharmacol. Res. Commun., 18:71; Halushka, et al. (1985), Elevated plasma 6-keto-prostaglandin F1 alpha in Patients in Septic Shock, Crit. Care Med., 13:451; Smedegard, et al. (1989), Endotoxin-induced Shock in the Rat: A Role for C5a, Am. J. Pathol., 135:489). It has been shown that animals pretreated with anti-TNF antibodies (Beutler et al. (1985), Passive immunization against cachectin/TNF protects mice from lethal effects of ET, Science, 229:869), PAF receptor antagonists (Casals-Stenzel (1987), Protective Effect of WEB 2086, a Novel Antagonist of Platelet Activating Factor in Endotoxin Shock, European J. Pharmacology, 135:117), and prostacyclin synthesis inhibitors (Wise, et al. (1985), Ibuprofen, Methylprednisolone, and Gentamycin as Cojoint Therapy in Septic Shock, Circ. Shock, 17:59) are protected against septic shock. However, the relative importance of these mediators in the pathology of septic shock is presently uncertain, which in turn renders them unpredictable for widespread clinical use, There is also evidence that some of these mediators may act indirectly via release of secondary mediators, in direct support of the finding that anti-TNF antibodies have little or no protective effect when given after ET exposure (Beutler, et al. (1985) Science, 229:8691).
The pathogenesis of the cardiovascular collapse that occurs during septic shock is poorly understood. Current treatment includes i.v. fluid administration and use of pressor drugs to increase peripheral vascular resistance and maintain organ perfusion. Very recently, endotoxin-binding agents including polymyxin B (Hanasawa, et al. (1989), New Approach to Endotoxic and Septic Shock by Means of Polymyxin B Immobilized Fiber, Surg. Gynecol. Obstet. 168:232) and antibodies which neutralize TNF (Tracey, et al. (1987), Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteremia, Nature, 330:662-664) have been used in an attempt to modify the sequelae of septic shock. The latter approach may have prophylactic value. However, no evidence exists that such an approach would be useful in reversing septic shock. The present inventors propose that therapy of patients already in septic shock requires intervention at secondary and tertiary steps in the cascade of events initiated by endotoxin.
The development of hypotension and other changes associated with septic shock may depend on complex interactions between cytokines, eicosanoids, PAF, activated complement components, and other factors. It is, therefore, not surprising that several interventions have been found to be at least partially effective in some models.
Increased circulating nitrogen oxides following interleukin-2 (IL-2) immunotherapy has been shown by Ochoa (1992) (J.N.C.I., 84:864-867). Ochoa et al. (J. Natl. Cancer Inst., 84:864-867 (1992)) have also shown that plasma nitrate levels are elevated about nine-fold in cancer patients receiving IL-2- and anti-CD3-activated lymphocytes. This increase in plasma nitrates correlated temporarily and quantitatively (albeit loosely) with the systemic hypotension characteristic of IL-2 administration. Although significant nitrate is present in a normal diet., Ochoa et al. assert that the increased plasma nitrate seen in anorexic patients reflects the overproduction of NO. by IL-2-induced nitric oxide synthase. Hibbs et al. (J. Clin. Invest. 89:867-877 (1992)) achieved even greater verification of this point by showing the conversion of [.sup.15 N]arginine to [.sup.15 N]nitrate. The possible contribution of decreased renal function to the observed increases in plasma nitrate was shown to be minimal (Ochoa (1992)). These studies and recently reported similar studies by Hibbs et al. ((1992) J. Clin. Invest., 89:867-877) definitively show cytokine-mediated induction of NO. synthesis in humans.
The findings of Ochoa et al. and Hibbs et al. described provide strong support for the view that the dose-limiting hypotension associated with the therapeutic use of IL-2 in humans is mediated by NO.. The studies also accord well with earlier studies by Wagner's group (PNAS (1983), 80:4518-4521), indicating that plasma and urinary nitrate levels increase in endotoxemic animals, an effect now attributable to the endotoxin-mediated induction of nitric oxide synthase (Ochoa et al. (1991) Ann. Surg., 214:621-626). It is notable that the findings in IL-2-induced hypotension and in septic shock are mechanistically related, since both IL-2 and endotoxin induce synthesis of IL-1 and tumor necrosis factor (Gento et al. (1988); Boccoli et al. (1990); Cancer Res. 50:2371-2374 (1990)), and that those cytokines have been shown to induce nitric oxide synthase in several systems (Kilbourn et al. (1990), PNAS, 87:3629-3632; Busse et al. (1990) FEBS Letts., 275:87-90; Kilbourn et al. (1990) J. Natl. Cancer Inst. 82:172-176 ).
While a variety of parenteral formulations have been described in the literature, some of which are compositionally modified so as to exclude arginine, none have been described for use in conjunction with anti-tumor necrosis factor antibodies, anti-endotoxin antibodies, or IL-1 receptor antagonists. Instead, formulations specially tailored for cancer patients to be used as a therapy for inhibiting tumor growth, such as those described by Ajani et al. are present in the art. Arqinine-free parenteral formulations have not been described as part of a combination therapy, particularly in a therapeutic regimen or method for the treatment of hypotension.
The considerations outlined above suggest that therapeutic approaches to NO.-mediated shock should (a) target the inducible isoform of nitric oxide synthase, (b) accommodate the ready and unregulated diffusion of NO., and (c) if possible, be particularly effective in limiting NO. production by vascular endothelium and smooth muscle. The present invention provides approaches which meet all of these goals with combination therapies that may be useful in the management of pathologies and conditions where hypotension and septic shock present a health risk.